Combinatorial methods for generating small molecule libraries coupled with high throughput screening have become core technologies for the identification of small molecule ligands to receptors and enzymes. The identified ligands serve as powerful tools for pharmacological studies and are essential to drug development. Combinatorial approaches have been most successful when information has been used to design the library of molecules to be prepared and tested. In these efforts, libraries are designed using knowledge of the mechanism or structure of the biological target, or by basing the library upon lead compound(s) that have previously been identified to bind to the biological target. Unfortunately, for many biological targets structural or mechanistic information is not available or does not provide sufficient insight to enable productive library design. Additionally, for many targets, lead compounds have not yet been identified or novel motifs for binding are desired. Not surprisingly, under these circumstances the preparation and screening of libraries has been much less successful, since we can prepare and test only an infinitesimally small fraction of the greater than 1060 small molecules that could theoretically be prepared. Herein, we propose the development of a powerful new approach to rapidly identify small molecule ligands to biological targets called combinatorial target-guided ligand assembly. The method involves four sequential, straightforward steps and does not rely on lead compounds nor does it require knowledge of the mechanism or structure of the biological target. (1) A set of potential binding elements is prepared wherein each molecule of the set must be soluble in aqueous solution at high concentrations and must incorporate a common chemical linkage group. (2) The set of potential binding elements is screened at high concentrations to identify all binding elements that interact even weakly with the biological target. (3) A combinatorial library of linked binding elements is prepared whereby the binding elements are connected using the common chemical linkage groups through a set of flexible linkers. (4) The combinatorial library of linked binding elements is screened to identify the tightest binding ligands.